Dysregulated signaling networks in HNSCC: novel mechanism-based approaches for HSNCC prevention and treatment There is an urgent need for new treatment options for HNSCC patients, considering that their overall 5-year survival is relatively low (50%) and has improved only marginally over the past 3 decades. The emerging knowledge of how the dysregulated function of signaling networks contributes to the initiation, malignant growth, and metastasis of HNSCC can now be exploited to identify novel mechanism-based anti-cancer treatments. mTOR as a novel molecular target for HNSCC treatment. We have shown that the persistent activation of the kinase Akt and its downstream target mTOR is a frequent event in HNSCC, and that inhibition of mTOR by the use of rapamycin causes the rapid apoptotic death of HNSCC tumors in multiple experimental HNSCC models, thereby inducing tumor regression. We have continued our concerted effort to use novel genetically-defined and chemically-induced carcinogenesis models to evaluate the effectiveness of mTOR inhibitors for the prevention and treatment of HNSCC. Co-targeting mTOR inhibition overcomes cetuximab resistance in HNSCC harboring PIK3CA and RAS mutations. Cetuximab, a monoclonal blocking antibody against the epidermal growth factor receptor EGFR, has been approved for the treatment of HNSCC. However, only few patients display a long-term response to cetuximab, which has prompted the search for mechanisms underlying cetuximab resistance and new therapeutic options to enhance cetuximab effectiveness in HNSCC. We have recently developed an experimental model to study cetuximab resistance in vivo, consisting in retro-engineering cetuximab-sensitive HNSCC cells to express PIK3CA and RAS oncogenes, both of which are identified in HNSCC lesions and can bypass EGFR growth promoting signaling. Cetuximab treatment of PIK3CA- and RAS-expressing HNSCC xenografts promoted an initial anti-tumor response, but all tumors relapsed within few weeks. In these tumors, cetuximab did not decrease the activity of mTOR, a downstream signaling target of EGFR, PIK3CA, and RAS. The combined administration of cetuximab and mTOR inhibitors exerted a remarkably increased anti-tumor activity, particularly in HNSCC cells that are resistant to cetuximab as a single agent. This study revealed that PIK3CA and RAS mutations and other genetic and epigenetic alterations affecting the mTOR pathway may predict the potential resistance to cetuximab. This information can now be also used to select the patients that may benefit the most from the concomitant administration of cetuximab and PI3K and/or mTOR inhibitors as a precision molecular therapeutic option for HNSCC patients. A key role for p38 MAPK in HNSCC growth, and tumor-induced angiogenesis and lymphangiogenesis. We have recently gained a remarkable understanding of the mutational landscape of HNSCC. However, the nature of the dysregulated signaling networks contributing to HNSCC progression is still not fully defined. We have recently focused on the role of the family of mitogen activated kinases (MAPKs), extracellular regulated kinase (ERK), c-Jun terminal kinase (JNK) and p38 MAPK in HNSCC. Immunohistochemical analysis of a large collection of human HNSCC tissues revealed that the levels of the phosphorylated active form of ERK1/2 and JNK were elevated in less than 33% and 16% of the cases, respectively. Strikingly, however, high levels of active phospho-p38 were observed in most (79%) of hundreds of tissues analyzed. We explored the biological role of p38 in HNSCC cell lines using three independent approaches: treatment with a specific p38 inhibitor, SB-203580; a retro-inhibition strategy consisting in the use of SB-203580 combined with the expression of an inhibitor-insensitive mutant form of p38&#945;; and short-hairpin RNAs (shRNAs) targeting p38&#945;. We found that specific blockade of p38 signaling significantly inhibited the proliferation of HNSCC cells both in vitro and in vivo. Indeed, we observed that p38 inhibition in HNSCC cancer cells reduces cancer growth in tumor xenografts and a remarkable decrease in intratumoral blood and lymphatic vessels. We conclude that p38&#945; functions as a positive regulator of HNSCC in the context of the tumor microenvironment, controlling cancer cell growth as well as tumor-induced angiogenesis and lymphangiogenesis. Genomic and proteomic approaches to understand oral cancer We have conducted gene and protein expression analysis of HNSCC by combining laser capture microdissection (LCM), gene arrays, next-gen sequencing and proteomic platforms. These efforts are providing a wealth of information about the dysregulated molecular circuitries driving HNSCC development, hence facilitating the identification of new therapeutic targets and suitable biomarkers for monitoring HNSCC progression and treatment response. Exploiting the head and neck cancer oncogenome. The recent development of deep sequencing approaches to study human cancer genomes in individual tumor lesions is already revolutionizing medical oncology and translational medicine. This large and growing body of information is now contributing to the elucidation of aberrant molecular mechanisms driving tumor progression, hence revealing novel druggable targets for therapeutic intervention to prevent and treat human cancers. The emerging picture is that despite the remarkable complexity of genomic alterations found in HNSCC, most of them fall within few major driver-signaling pathways, with the majority of the HNSCC lesions harboring genetic and epigenetic alterations that converge on the persistent activation of the PI3K-mTOR pathway. While representing a major HNSCC driver, this likely overreliance on the PI3K-mTOR signaling route for tumor growth can in turn expose a cancer vulnerability that can be exploited for therapeutic purposes. Indeed, the have documented the sensitivity of HNSCC to mTOR inhibition in multiple experimental models and encouraging recent clinical studies. The presence of genomic alterations in the PI3K pathway may also represent a suitable biomarker predicting a clinical response to its pharmacological inhibitors.